EP0547166A1 - Therapie par cellules t cytotoxiques (ctl) specifiques d'agents pathogenes - Google Patents

Therapie par cellules t cytotoxiques (ctl) specifiques d'agents pathogenes

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Publication number
EP0547166A1
EP0547166A1 EP91918302A EP91918302A EP0547166A1 EP 0547166 A1 EP0547166 A1 EP 0547166A1 EP 91918302 A EP91918302 A EP 91918302A EP 91918302 A EP91918302 A EP 91918302A EP 0547166 A1 EP0547166 A1 EP 0547166A1
Authority
EP
European Patent Office
Prior art keywords
pathogen
cells
ctl
infected
mammal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP91918302A
Other languages
German (de)
English (en)
Other versions
EP0547166A4 (fr
Inventor
Judy Lieberman
Malcolm Gefter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
New England Medical Center Hospitals Inc
Immulogic Pharmaceutical Corp
Original Assignee
New England Medical Center Hospitals Inc
Immulogic Pharmaceutical Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by New England Medical Center Hospitals Inc, Immulogic Pharmaceutical Corp filed Critical New England Medical Center Hospitals Inc
Publication of EP0547166A1 publication Critical patent/EP0547166A1/fr
Publication of EP0547166A4 publication Critical patent/EP0547166A4/xx
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/464838—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule

Definitions

  • This invention relates to therapies involving administration of cytotoxic T lymphocytes.
  • Cytotoxic T cells that specifically lyse HIV-1 infected autologous target cells have been found to occur at uncommonly high frequency in the blood of HIV- infected individuals; killing by such cells is predominantly mediated by CD3 + CD8 + effector cells although cytotoxic CD4 + cells and natural killer cells also play a role (Walker et al.. Nature 328:345 1987; Plata et al., Nature 328:348, 1987; Walker et al., Science 240:64, 1988; Sethi et al., Nature 335:178. 1988; Koenig et al. , Proc . Natl . Acad. S i .
  • CD8 + T cells recognize antigenic peptides presented by MHC class I molecules.
  • a peptide must be properly processed, be capable of binding to MHC strongly enough to compete with other peptides, and be recognized as a peptide-MHC complex by T cells in the repertoire.
  • Recent studies indicate that in some infections only a small number of peptides meet these criteria and that CTL specific for these epitopes dominate the lytic response (Braciale et al. , Immunol . Rev. £8:95, 1987; Whitton et al., J. Virol . j52:687, 1988; Klavinskis et al., J. Virol .
  • the invention features a method of treating a mammal infected with an intracellular pathogen involving selecting, from a sample of the mammal's lymphocytes, a sub-sample which is enriched for cytotoxic T lymphocytes which recognize a pathogen-specific antigen and which are capable of lysing pathogen-infected cells of the patient, and administering to the patient a therapeutically effective amount of the sub-sample of cytotoxic T lymphocytes.
  • Preparation of such a pathogen- specific CTL-enriched sub-sample generally involves stimulating the proliferation of a mammal's T-lymphocytes in vitro, using a nonspecific mitogen, in the presence of pathogen-infected cells (i.e., cells displaying pathogen- specific antigens on their surfaces) ; inclusion of such pathogen-infected cells results in the selective expansion of a population of CTL's which are capable of targeting and lysing host cells harboring the patl _ .
  • pathogen-infected cells i.e., cells displaying pathogen- specific antigens on their surfaces
  • Preparation of the pathogen-specific CTL-enriched sub- sample may further involve identifying, for a particular mammal, those pathogenic-specific antigens which are capable of eliciting a particularly potent CTL response and presenting peptides displaying these antigens to the proliferating T cells in order to further expand the pathogen-specific CTL population in the sub-sample.
  • the sub-sample is prepared by incubating the sample with a mitogen which is capable of inducing lymphocyte proliferation (preferably, phyt ⁇ hemagglutinin) ; the sample is further incubated with IL-2; the sample is further contacted with a pathogen- specific antigen recognized by CTL's of the mammal and which is capable of inducing a CTL response the mammal; the method further involves adminit. ing to the mammal a therapeutically effective amount of a pathogen- specific antigen recognized by the CTL's of the mammal and which is capable of stimulating a cytotoxic T lymphocyte response in the mammal.
  • a mitogen which is capable of inducing lymphocyte proliferation preferably, phyt ⁇ hemagglutinin
  • the invention fe; * ⁇ ures a method of treating a mammal infected with an intracellular pathogen involving administering to the mammal a therapeutically effective amount of a pathogen-specific antigen which is recognized by the CTL's of the mammal and which is capable of stimulating a cytotoxic T lymphocyte response in the mammal.
  • the antigen is displayed on the surface of an autologous antigen-presenting cell (preferably a B-lymphocyte) ;
  • the mammal is a human;
  • the intracellular pathogen is a virus (preferably a human immunodeficiency virus, a human T cell leukemia virus, or a Herpes virus, preferably, an Epstein-Barr virus) , a mycobacterium, a protozoan, or a fungus; and the pathogen-specific antigen ⁇ - ⁇ im unodominan .
  • the pathogen-specific antigen is preferably an HIV-encoded protein (for example, the product of the env or the pol gene) , or a CTL-stimulatory fragment thereof.
  • intracellular pathogen is meant a disease- causing organism which resides, during at least a part of its life cycle, within a host cell.
  • enriched for cytotoxic T lymphocytes is meant that the sub-sample has a substantially greater number of pathogen-specific cytotoxic T lymphocytes (i.e., T lymphocytes which recognize and destroy cells bearing foreign antigens, in this case, pathogen-specific antigens, on their surfaces) than a freshly isolated sample of the patient's lymphocytes.
  • pathogen-specific antigen is meant a protein produced upon infection by a pathogen which is recognized (i.e., responded to) as foreign by cells, in this case, cytotoxic T cells, of the patient's immune system.
  • pathogen is meant to destroy or disintegrate, for example, a host cell harboring a pathogen.
  • pathogen-infected cells is meant those host cells harboring a pathogen, either in an active or a latent state.
  • mitogen is meant a substance that stimulates mitosis and, thus, cell proliferation.
  • CTL response is meant the proliferation of CTL's in response to, and specific for, a stimulatory antigen.
  • autologous is meant occurring in the same patient.
  • antigen- presenting cell is meant any cell capable of displaying on its cell surface an antigen, or an immunogenic fragment thereof.
  • human immunodeficiency virus is meant, without limitation, HIV-l and HIV-2;
  • human T cell leukemia virus is meant, without limitation, HTLV- I and HTLV-II;
  • Herpes virus is meant, without limitation, Herpes simplex type 1 and type 2, Herpes zoster, and cytomegalovirus as well as Epstein-Barr virus.
  • virus is also meant, without limitation, Papillomavirus, Creutzfeldt-Jakob virus, and feline leukemia virus.
  • mycobacterium is meant, without limitation, Mycobacterium leprae, Mycobacterium tuberculosis.
  • protozoan is meant, without limitation, Toxoplas a gondii, Giardia lamblia, Trvpanosoma cruzi, organisms of the genus Leishmania, and organisms of the genus Plasmodium which cause malaria.
  • fungus is meant, without limitation, Pneumocystis carinii f Candida albicans, and Candida tropicalis.
  • CTL-stimulatory fragment is meant a peptide which is capable of stimulating antigen-specific CTL proliferation.
  • immunodominant is meant (an antigen) capable of eliciting an unusually potent CTL response.
  • the CTL's of the enriched sub-sample or CTL's expanded in the host following administration of pathogen-specific CTL- stimulatory peptide or peptide-bearing antigen-presenting cells recognize and selectively target pathogen-infected cells. Because such pathogen-infected cells represent a small percentage of the total cell population, this method minimizes side effects, such as immunosuppression, which may result from other forms of therapy such as those which destroy or impair the function of host cells which are either infected or at risk of being infected by the pathogen.
  • the pathogen-specific CTL population may be administered to the mammal free of lymphokines, thereby avoiding the vascular-leak syndrome generally associated with lymphokine therapies, at least in humans and mice.
  • the pathogen-specific CTL population is generated from a mammal's lymphocyte sample. This is an important feature of the invention because antigens capable of inducing an effective CTL response (i.e., inducing significant CTL proliferation) may vary, and, for example, in the case of HIV-1, do vary from one individual to the next. .
  • Fig. 1 is a diagrammatic representation of a set of truncated HIV-1 envelope and reverse transcriptase proteins, from which can be derived peptides which are useful as candidate HIV-1-specific, CTL-stimulatory antigens.
  • Fig. 2 is a schematic representation of the HIV-
  • the method generally involves establishing a T cell line (i.e., population) from a sample of the patient's lymphocytes and stimulating proliferation of this T cell line with a nonspecific mitogen.
  • a T cell line i.e., population
  • HIV-l infected cells i.e., cells displaying HIV-l antigens on their surface
  • the final preparation is enriched for cytotoxic T lymphocytes, which recognize and lyse cells displaying an HIV-l specific antigen.
  • the method may further involve identifying, for a particular patient, an immunodominant HIV-l specific antigen(s) which is(are) capable of inducing a CTL response and presenting a peptide(s) displaying this epitope to the proliferating T cell line to further enrich the sub-sample for HIV-l specific CTL's.
  • Heparinized whole blood was obtained from HIV-l infected patients, i.e., patients seropositive for HIV-l as assayed by Western blot analysis, and peripheral blood lymphocytes (PBLs) were isolated by Ficoll-Hypaque density centrifugation.
  • PBLs peripheral blood lymphocytes
  • Cells were cultured at 5xl0 5 /ml in RPMI 1640 supplemented with 15% fetal calf serum (Hazleton) , 2mM HEPES, 2mM glutamine, 100 U/ml penicill ' , 100 ⁇ g/ml strep t omycin, and 50 ⁇ M ⁇ - mercapto ⁇ _chanol, and T cell lines were established by addition of 2 ⁇ g/ml PHA-P (Difco) and 200 U/ml rhu IL2 (Cetus) . Twice a week cultures were adjusted to 5xl0 5 /ml with fresh IL-2-containing media.
  • Hazleton fetal calf serum
  • 2mM HEPES 2mM glutamine
  • 100 U/ml penicill ' 100 ⁇ g/ml strep t omycin
  • 50 ⁇ M ⁇ - mercapto ⁇ _chanol T cell lines were established by addition of 2
  • T cell lines were generated from ten CDC group II, five group III and three CDC group IV individuals. These cell lines grew vigorously for over a month without further stimulation, even from patients with AIDS, although those cells grew less vigorously. After 6 weeks, most cell lines with no f. -.her exogenous stimulation had stopped dividing. No T cexl line could be generated from one hemophiliac patient with longstanding AIDS and profound immunodeficiency (absolute CD4 count 20/mm 3 , CD4/CD8 ratio 0.03).
  • T cell lines were screened for cytotoxicity against autologous B cell lines infected with vaccinia virus containing the HIV-l env gene or a fragment of the pol gene (i.e., constructs vPE16 and vCF21, respectively, described in Walker et al. , 1987, supra; Walker et al., 1988, supra) ; a B cell line infected with a vaccinia virus containing the lacZ gene was used as a control (i.e., construct vSC8, described in Chakrabarti et al. , Nature 320:535. 1986; Flexner et al., Virol . 166:339, 1988).
  • construct vSC8 described in Chakrabarti et al. , Nature 320:535. 1986; Flexner et al., Virol . 166:339, 1988.
  • EBV- transformed B cell lines were generated from the patient's peripheral blood lymphocyte samples by standard techniques using B95-8 marmoset cell line supernatant.
  • Env-vaccinia (vPE16)-infected cells expressed the gpl20 and gpl60 (env) proteins from isolate HIV-1 IIIB ;
  • pol- vaccinia (vCF21)-infected cells expressed all but the last 22 amino acids of the reverse transcriptase (RT) protein from isolate HIV-l H ⁇ 2 .
  • RT reverse transcriptase
  • Vaccinia virus was prepared and titered by plaque forming assay on CV-l cells as described in Mackett, M. , et al. ("The construction and characterization of vaccinia virus recombinants expressing foreign genes", in D. Glover, ed. , DNA cloning: A practical approach, Vol II, IRL Press, Oxford, 1985) . Env-vaccinia infected cells were, in some cases, also titered by assaying syncytia formation upon cocultivation with C8166 cells (as described in Salahuddin et al., Virology 129, 51, 1983).
  • vaccinia virus infection 1-4 pfu/cell of virus was added to 5xl0 5 exponentially growing B cells in 500 ul of media in a 24 well microtiter plate. Cells were incubated, with rocking, at 37°C over C0 2 for 30 min; an additional 1 ml of media was added to each well, and cells were further incubated, without rocking, for 16 hr.
  • Cytotoxicity was measured using a 51 -Chromium (Cr) release assay as follows.
  • B ⁇ ells i.e., target cells
  • B ⁇ ells i.e., target cells
  • serum-containing media to which was added lOOuCi of Na 2 ( 51 Cr0 4 ) (Dupont) .
  • targets were washed 3 times and resuspended at 10 5 cells/ml.
  • 10 4 labelled targets were added to triplicate wells of U bottom microtiter plates. For peptide experiments, the labelled targets were incubated with peptide at a final concentration of 50 ⁇ g/ml for 30 min.
  • T cell lines directed as much as 40% HIV-1-specific cell lysis above background (i.e., lacZ target) lysis in a 4 hr assay using an effector:target (E:T) ratio of 6:1. This was in contrast to autologous, freshly isolated peripheral blood lymphocytes which, from some patients, showed little or no HIV-specific lysis.
  • E:T effector:target
  • the PHA- stimulated T cell lines Prior to enhanced HIV-1-specific killing, the PHA- stimulated T cell lines acquired NK-like activity, presumably in response to the supraphysiological concentration of IL-2; this effect declined over time in culture.
  • the cultured T cell line was further stimulated with a peptide which included an immunodominant HIV-1-specific epitope recognized by the patient*s CTL.
  • his/her established T cell line was screened after 2-5 weeks in culture for cytotoxicity against autologous B cell targets infected with the vaccinia virus constructs encoding nested truncations of env and RT proteins; cytotoxicity was assayed by 51 Cr- release.
  • the epitope was further defined by assaying cytotoxicity (again, by 51 Cr-release) against autologous targets which presented short overlapping peptides spanning the region identified as immunodominant using truncated proteins.
  • a representative set of vaccinia vectors expressing nested truncations of the above env and RT isolates are shown in Fig. 1.
  • response to a single 104 amino acid region i.e., amino acids 747 to 151 of the env glycoprotein unequivocally dominated cytolysis; in one cell line, an additional region (i.e., 1 to 204) was also recognized.
  • an additional region i.e., 1 to 204
  • a set of seven 22-amin ⁇ acid peptides with 8-amino acid overlaps spanning this region was synthesized by standard techniques (by scientists other than, the named inventors) and used to sensitize autologous 51 Cr-labelled targets.
  • T cell lines that recognized determinants in this region responded to different peptide epitopes.
  • a peptide concentration of 0.2 ⁇ g/ml was needed to begin to sensitize targets and the response plateaued at 12 ⁇ g/ml.
  • three separate T cell lines generated over a period of six months consistently recognized the same single dominant epitope.
  • the T cell line from another subject analyzed with a set of 20- amino acid peptides with 10-amino acid overlaps (obtained from the MRC AIDS Reagent Project) , also recognized a single peptide (i.e., amino acids 219 to 238).
  • HIV-l isolate used as a source of candidate CTL-stimulatory antigens is likely different from the HIV-l isolates harbored by the patient and because at least some HIV-l proteins vary considerably in amino acid sequence between isolates, it is likely that viral antigens identified by this method, e.g., those described above, are relatively invariant.
  • peptides bearing these epitopes were used to stimulate CTL proliferation as follows. T cell lines (approximately 3-4 weeks after initiation of culture' were harvested and resuspended in fresh IL-2-containing media at 10 6 cells/ml.
  • peptide lines were selected with either peptide alone (by adding.an equal volume of peptide-containing media to a final concentration of 1- 50 ⁇ g/ml) or peptide presented by autologous antigen- presenting B cells.
  • B cell lines were irradiated (5000 rad) , resuspended at 10 6 /ml and incubated with peptide at 1-50 ⁇ g/ml at 37°C with occasional mixing. After 2 hr, the incubated cells were pelleted and added to the T cell line in an equal volume of fresh media. Twice weekly, T cells were counted and fresh media added to maintain a cellular concentration of 5xl0 5 /ml. After 10 days, treated T cell lines were tested for cytotoxicity against vaccinia-infected targets.
  • T cell line 132 derived from a patient with generalized lymphadenopathy, was shown to recognize both an N-terminal and a C-terminal epitope in env but none in RT.
  • a three week T cell line from this individual was incubated either directly with the C-terminal env peptide that it recognized (i.e., amino acids 802-823 of sequence, YWWNLLQYWSQELKNSAVNLLN) or with irradiated autologous B cells preincubated with this peptide and washed to remove unbound peptide.
  • Sub-samples enriched for pathogen-specific CTL's are administered to a pathogen-infected patient as follows. Cells are washed with PBS to remove culture medium and are infused back into the patient by the standard techniques developed for cancer therapy by Rosenberg (see, e.g., Rosenberg et al., N. Eng. J. Med . 319:1676. 1988). Typically, infusion is performed intravenously using 10 9 - 10 11 cells, and the procedure takes approximately 30 minutes. If necessary, treatment can be repeated. Therapy can be administered soon after pathogen infection or upon onset of symptoms. In addition, one or more PBL samples isolated from a pathogen-infected, asymptomatic individual, or a CTL- enriched sub-sample prepared following pathogen infection, may be stored, frozen in liquid nitrogen, until such time as that patient requires therapy.
  • the CTL's of the enriched sub-sample recognize and selectively target pathogen-infected cells and because such pathogen-infected cells represent a small percentage of the total cell population, this method minimizes side effects resulting from generalized cell damage.
  • the enriched CTL sub-sample would target HIV- infected CD4 lymphocytes, monocytes and macrophages, leaving other cells of the immune system (including uninfected CD4-bearing lymphocytic and monocytic cells) intact and thus reducing the risk of im unosuppression.
  • This method also avoids the side, effects, e.g., the vascular-leak syndrome associated with lymphokine therapy.
  • CTL-stimulatory pathogen-specific antigens e.g., peptides including immunodominant epitopes
  • a pathogen- infected patient either as a purified peptide or as a processed antigen presented on the surface of an irradiated autologous antigen-presenting cell (e.g., irradiated autologous B cells or autologous PBLs, incubated with peptide antigen as described in the above example) .
  • an irradiated autologous antigen-presenting cell e.g., irradiated autologous B cells or autologous PBLs, incubated with peptide antigen as described in the above example
  • such a peptide antigen would be mixed with a pharmaceutically acceptable carrier (e.g., physiological saline) and administered to a patient by the standard procedures, e.g., intravenous injection.
  • a pharmaceutically acceptable carrier e.g., physiological saline
  • irradiated antigen-presenting cells would be infused back into a patient by the standard techniques of Rosenberg (supra) as described above.
  • CTL-stimulatory pathogen- specific antigens may be administered (as described above) at any time following infusion, with a pathogen- specific CTL-enriched sub-sample to further stimulate the pathogen-specific CTL response.
  • lymphokines such as IL-2 or IL- 4 may be co-administered with either pathogen-specific CTL-stimulatory peptides or sub-samples of pathogen- specific CTL-enriched lymphocytes to further enhance lymphocyte proliferation.
  • a patient may be treated with antihistamines, aspirin or acetaminophen, prior to administration of lymphokines.
  • a patient may be treated with cyclophosphamide prior to administration of _ ⁇ ithogen-specific CTL-stimulatory peptides or pathogen-specific CTL's.
  • Pathogen-specific CTL's can combat pathogen infection by recognizing and lysing cells infected with pathogen, thereby preventing further spread of infection.
  • certain pathogen-specific CTL's e.g., CTL's specific for Epstein-Barr virus, can be used to prevent or to treat a virus-induced ly phoma in a patient infected with EBV alone or in a patient infected with EBV and a human immunodeficiency virus.
  • PBLs may be gro ⁇ ,n human serum-containing medium or, alternatively, in rum-free medium (e.g., AIM V, Gibco) .
  • Mitogens other than PHA e.g., concanavalin A, anti-CD3 monoclonal antibody, or anti-T cell receptor monoclonal antibody
  • ly Dhokines other than IL-2 e.g., IL-4
  • Any expression vector capable of transfecting or infecting an antigen-presenting cell may be used in this invention.
  • CTL-stimulatory antigens may be included in HIV- l-encoded proteins other than env and RT, e.g., they may be included in the gag or nef proteins.
  • gag, nef, or in any HIV-l-encoded protein a complete set of candidate peptides would be prepared by fragmenting HIV-l cDNA, cloning each fragment into a vaccinia expression vector (or any appropriate expressi -n vector as defined above) , and testing for CTL-stimulatory capability as described in the above e x ample.
  • candidate peptides may a synthesized in vitro and tested for CTL-stimulatory activity as described in the above example.
  • An epitope domain could be further refined by expressing sub-fragments of the cloned DNA or by synthesizing sub-fragments of the candidate peptides, which span the immunogenic region. Large numbers of fragments could be tested simultaneously by attaching candidate peptides to a series of microtiter wells, adding 51 Cr-labelled autologous target cells, adding an aliquot of a patient's T cells to each well, and screening for cytotoxicity.
  • Fragments shown to encode a CTL-stimulatory peptide would be administered directly to the patient (as a peptide or presented on the surface of an irradiated, autologous antigen-presenting cell) or would be used to selectively expand an HIV-l- specific CTL population in a sample of a patient's peripheral blood lymphocytes.
  • Any isolate of HIV-l may be used as a source of candidate viral-specific antigens, and a patient infected with any isolate of HIV-l (e.g., HIV-l ⁇ j ) may be treated using the methods of this invention.
  • Proteins or protein fragments homologous to HIV-l-encoded proteins may also be useful in this invention if such proteins or fragments elicit an HIV-1- specific CTL response; such proteins may be coded for by other primate lentiviruses, e.g., HTLV-I and HTLV-II as well as the simian immunodeficiency viruses.
  • T cell lines or pathogen-infected patients may be presented simultaneously with more than one pathogen-specific CTL- stimulatory epitope; such epitopes may be resident in the same or in different proteins.
  • any pathogen-infected mammal may be treated with a therapeutic amount of a CTL-stimulatory pathogen-specific antigen or with a sub-sample of the mammal's lymphocytes enriched for CTL's which recognize and lyse cells bearing such an antigen, using the methods described above.
  • these methods can be used to identify CTL-stimulatory antigens of, and to treat human patients or mammals infected with, other pathogenic viruses including, but not limited to, HIV-2, human T- cell leukemia viruses, Herpes viruses (e.g., Epstein- Barr virus) as well as any intracellular disease-causing mycobacterium, protozoan, or fungus.
  • pathogen-specific CTL's would be prepared as described above for HIV-l, i.e., by culturing a patient's lymphocytes in the presence of pathogen-infected cells or in the presence of one or more CTL-stimulatory pathogen- specific epitopes.
  • a sample of the patient's or mammal's cells which harbor pathogen would be isolated by standard techniques and co-cultured with a sample of the patient's or mammal's lymphocytes to produce a pathogen-specific CTL-enriched lymphocyte sub-sample.
  • Pathogen-specific antigens may be presented to T cells in processed form on the surface of an antigen- presenting cell other than a B-lymphocyte, e.g., on the surface of an autologous PBL or an autologous cell of monocytic lineage.

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Abstract

L'invention décrit un procédé de traitement d'un malade infecté par un agent pathogène intracellulaire, qui comprend l'administration au malade d'un antigène stimulateur des lymphocytes T cytotoxiques spécifiques d'agents pathogènes intracellulaires, ou une préparation des lymphocytes du malade enrichie par des lymphocytes T cytotoxiques, spécifiques d'agents pathogènes intracellulaires.
EP91918302A 1990-09-06 1991-09-06 Therapie par cellules t cytotoxiques (ctl) specifiques d'agents pathogenes Ceased EP0547166A1 (fr)

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US578828 1984-02-10
US57882890A 1990-09-06 1990-09-06
CA002089488A CA2089488A1 (fr) 1990-09-06 1991-09-06 Agent pathogene pour therapie cytotoxique

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EP0547166A4 EP0547166A4 (fr) 1994-03-09

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Families Citing this family (9)

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Publication number Priority date Publication date Assignee Title
US5346989A (en) * 1990-08-22 1994-09-13 Syntello Vaccine Development Kb Peptides for use in induction of T cell activation against HIV-1
WO1992021377A1 (fr) * 1991-06-03 1992-12-10 Syntello Inc. Peptides a utiliser pour induire l'activation de lymphocytes t contre le vih-1
US7300660B2 (en) 1993-11-23 2007-11-27 The Regents Of The University Of California Abundant extracellular products and methods for their production and use
US6752993B1 (en) 1993-11-23 2004-06-22 The Regents Of The University Of California Abundant extracellular product vaccines and methods for their production and use
AU1097795A (en) 1993-11-23 1995-06-13 Regents Of The University Of California, The Abundant extracellular products and methods for their production and use
WO1997007128A1 (fr) * 1995-08-21 1997-02-27 Duke University Procede pour accroitre la densite d'un antigene sur une cellule presentant un antigene
US5994308A (en) * 1996-02-28 1999-11-30 Board Of Trustees Of Southern Illinois University Broad spectrum antimicrobial peptides containing a tryptophan triplet and methods of use
US6013660A (en) * 1996-10-02 2000-01-11 The Regents Of The University Of California Externally targeted prophylactic and chemotherapeutic method and agents
DE19710496A1 (de) * 1997-03-13 1998-09-17 Boehringer Mannheim Gmbh Verfahren zum Nachweis antigenspezifischer T-Zellen nach Anreicherung von mononukleären Zellpopulationen

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0260714A2 (fr) * 1986-09-19 1988-03-23 Oncogen Limited Partnership Utilisation de lymphocytes T actives dans la préparation d'un médicament pour le traitement du SIDA

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Publication number Priority date Publication date Assignee Title
EP0260714A2 (fr) * 1986-09-19 1988-03-23 Oncogen Limited Partnership Utilisation de lymphocytes T actives dans la préparation d'un médicament pour le traitement du SIDA

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
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See also references of WO9204462A1 *

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AU660422B2 (en) 1995-06-29
CA2089488A1 (fr) 1993-03-07
WO1992004462A1 (fr) 1992-03-19
AU8737991A (en) 1992-03-30
EP0547166A4 (fr) 1994-03-09

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